Diabetes and cardiovascular disease

Kausik Ray, MD

Imperial College London,

London, United Kingdom

DM and CVD Risk

Professor Kausik Ray

BSc, MBChB. MD, Mphil, FRCP (Lon), FRCP (Ed), FACC, FESC, FAHA

Professor of Public Health

School of Public Health, Imperial College London, UK

IDF diabetes atlas, 4th edition, 2009

2010 2030

Total number of people with diabetes (age 20-79)

285 million 438 million

Prevalence of diabetes (age 20-79)

6.6 % 7.8 %

Prevalence of diabetes in 2030

Coronary heart disease

Coronary death

Non-fatal myocardial infarction

Cerebrovascular disease

Ischaemic stroke

Haemorrhagic stroke

Unclassified stroke

Other vascular deaths

2.00 (1.83 - 2.19)

2.31 (2.05 - 2.60)

1.82 (1.64 - 2.03)

1.82 (1.65 - 2.01)

2.27 (1.95 - 2.65)

1.56 (1.19 - 2.05)

1.84 (1.59 - 2.13)

1.73 (1.51 - 1.98)

HR (95% CI)

26 505

11 556

14 741

11 176

3799

1183

4973

3826

Number

of cases

64 (54-71)

41 (24-54)

37 (19-51)

42 (25-55)

1 (0-20)

0 (0-26)

33 (12-48)

0 (0-26)

I2 (95% CI)

11 2 4

Hazard ratio (diabetes vs. no diabetes)

Outcome

Lancet. 2010 Jun 26;375(9733):2215-22

Diabetes doubles the risk of vascular diseaseData from 528,877 participants (adjusted for age sex, cohort, SBP, smoking, BMI)

Diabetes risk is not explained by conventional risk factors

Ischaemic stroke

Age and sex

Plus smoking status

Plus BMI

Plus SBP

Plus non-HDL-C

Plus HDL cholesterol

Plus log-triglycerides

2.06 (1.82-2.34)

2.10 (1.85-2.39)

2.00 (1.78-2.25)

1.91 (1.70-2.14)

1.93 (1.71-2.16)

1.87 (1.67-2.09)

1.87 (1.67-2.09)

HR (95% CI)

11 2 4

2.56 (2.15-3.05)

2.59 (2.16-3.09)

2.45 (2.08-2.88)

2.27 (1.94-2.65)

2.26 (1.94-2.64)

2.24 (1.94-2.60)

2.24 (1.94-2.59)

11 2 4

HR (95% CI)Adjusted for Coronary heart disease

11 2 4 11 2 4

Hazard ratio (diabetes vs. no diabetes)

Lancet. 2010 Jun 26;375(9733):2215-22

DM duration matters to CVD

Men with diabetes without MI Men with MI

None

N=3197

Late onset

N=307

Mean duration

1.7 years

Early onset

N=107

Mean duration

16 years

Without

diabetes

N=368

CVD events (n=534)

Age 1.00 1.59 (1.19,2.12) 2.61 (1.73,3.96) 2.35 (1.88,2.95)

Adj 1.00 1.53 (1.15,2.06) 2.52 (1.65,3.84) 2.23 (1.76,2.83)

Wannamethee, Shaper, Whincup, Lennon, Sattar (Archives Int Med in press)

Type 2 diabetes increases CHD/CVD risk over time

• CVD/CHD risk at or prior to diagnosis is determined by conventional CHD risk factors

• Hyperglycaemia in the diabetic range increases CHD risk over time

• After a diabetes duration of >8 years CHD risk equivalence is reached

Sattar N. Diabetologia 2013;56:686-695.

CH

D r

isk

Age

Diagnosis

~8–10years’

duration

CHD equivalence threshold

Prevention of Diabetes becomes increasingly essential

Why ?

• CV risk is incompletely explained by conventional risk factors

• Prognosis is worse with duration

How ?

• Tackling Obesity/ sedentary lifestyle/ caloric intake

• Legislation

Question: 1 what modality is best to lower CVD risk in DM ?Question: 2 how intensive should therapy be?

• Lipid-lowering?

• Blood pressure?

• Glucose-lowering?

• Aspirin?

• Lifestyle ?

Statins- reduce CV events consistently(per 39mg/dl lower LDL-C)

CTT Lancet 2008 ,371, 117-25

Time to First Major Cardiovascular Event in Patients With Diabetes

*CHD death, nonfatal non–procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke

HR = 0.75 (95% CI

0.58, 0.97)

P=0.026Atorvastatin 10 mg

Atorvastatin 80 mg

0 1 2 3 4 5 6

Time (years)

0.20

0.10

0.15

0.05

0

Cum

ula

tive

incid

ence

of

majo

r card

iovascula

r e

vents

*

Relative risk reduction = 25%

Fibrates ?

Fibrates and CVD risk reduction among those with atherogenic dyslipidemia

TG>200mg/dl and HDL <39mg/dl

Sacks et al NEJM 2010

Summary on lipids in T2DM

• Statin therapy remains the best lipid modifying agent

• Lower cholesterol targets (intensive statins) based on absolute risk. 50% LDL-C reduction or LDL-C <70mg/dl or 30%/ 100mg/dl in lower risk

• Fibrates, used as monotherapy or in combination therapy may have CVD benefit among those with atherogenic dyslipidemia and DM

Outline

• What treatments reduce CVD risk in Diabetes?

• Lipid-lowering?

• Blood pressure?

• Glucose-lowering?

• Aspirin?

Diabetics derive similar proportional reductions in risk as non-diabetics with BP lowering

BP treatment Trialists. Archives 2005, 165, 1410-1419

UKPDS lowering SBP reduces principally Strokes

BMJ 1998;317:703-713

ACCORD

Average after 1st year: 133.5 Standard 119.3 Intensive, Delta = 14.2

NEJM 2010, 362, 1575-1585

Primary & Secondary Outcomes

Intensive Events (%/yr)

StandardEvents (%/yr) HR (95% CI) P

Primary 208 (1.87) 237 (2.09) 0.88 (0.73-1.06) 0.20

Total Mortality 150 (1.28) 144 (1.19) 1.07 (0.85-1.35) 0.55

CardiovascularDeaths

60 (0.52) 58 (0.49) 1.06 (0.74-1.52) 0.74

Nonfatal MI 126 (1.13) 146 (1.28) 0.87 (0.68-1.10) 0.25

Nonfatal Stroke 34 (0.30) 55 (0.47) 0.63 (0.41-0.96) 0.03

Total Stroke 36 (0.32) 62 (0.53) 0.59 (0.39-0.89) 0.01

NEJM 2010, 362, 1575-1585

BP summary

• Actual BP achieved critical rather than agent used

– Meta-analysis

• Target BP <140/90 SBP for all

• More intensive target < 120 SBP results in stroke benefits

Outline

• What treatments reduce the CVD risk in Diabetes?

• Lipid-lowering?

• Blood pressure?

• Glucose-lowering?

• Aspirin?

Long-term beneficial effects on CVD risk following intensive treatment: DCCT/EDIC

0.12

0.10

0.08

0.06

0.04

0.02

0.00

Years since entry

Conventional therapy

Intensive therapy

1 2 3 4 5 6 7 8 9 10 11 12 210

Cu

mu

lati

ve in

cid

ence

of

any

pre

def

ined

card

iova

scu

lar

ou

tco

me

705714

683688

629618

11392

Intensive therapyConventional therapy

No. at risk

*Nonfatal MI or stroke; CV death; subclinical MI; angina; or the need for revascularization with angioplasty or coronary-artery bypass

13 14 15 16 17 18 19 20

42% risk reductionP=0.02

EDIC mean HbA1c over 11 years follow-up: 8.2%

EDIC mean HbA1c over 11 years follow-up: 8.0%

Nathan DM et al. N Engl J Med. 2005;353:2643-2653

Endpoints UKPDS PROactive ADVANCE VADT ACCORD Overall

Av FU 10.1 2.9 5.0 5.6 3.5 4.95

Person years of FU

46 237 15 059 55 700 10 030 35 879 162 905

Difference HbA1c (%)

0.9 0.6 0.5 1.5 1.1 0.9

NF- MI 362 263 309 142 421 1495

CHD 685 366 647 167 453 2318

Strokes 238 193 484 64 148 1127

Death from any cause

842 363 1031 197 460 2892

Ray KK, et al. Lancet. 2009;373:1765-1772

Effects of more vs less intensive control of glucose on non-fatal MI, CHD, stroke and mortality

I2=0% (95% CI 0-69.3%), p=0.61

Overall

ADVANCE

ACCORD

PROactive

VADT

UKPDS

21.86

28.86

9.44

21.81

0.83 (0.75, 0.93)

0.98 (0.78, 1.23)

0.78 (0.64, 0.95)

0.83 (0.64, 1.06)

0.81 (0.58, 1.15)

0.78 (0.62, 0.98)

100.00

28.86

18.03

1.4 .6 .8 1.2 1.4 1.6 1.8 2

Odds Ratio

Study

Intensive therapy better Standard therapy better

Weight

(%)

Odds Ratio

(95% CI)

Non-fatal MI

I2=0% (95% CI 0-53%), p=0.78

Overall

UKPDS

PROactive*

Study

ACCORD

ADVANCE

VADT

0.85 (0.77, 0.93)

Odds Ratio

(95% CI)

100.00

20.22

25.68

36.48

9.03

0.75 (0.54, 1.04)

0.81 (0.65, 1.00)

0.82 (0.68, 0.99)

0.92 (0.78, 1.07)

0.85 (0.62, 1.17)

8.59

Weight

(%)

1.4 .6 .8 1.2 1.4 1.6 1.8 2

Odds RatioIntensive therapy better Standard therapy better

CHD

I2=0% (95% CI 0-62%), p = 0.70

Overall

ACCORD

ADVANCE

PROactive†

UKPDS

VADT†

0.93 (0.81, 1.06)

1.05 (0.76, 1.46)

0.91 (0.51, 1.61)

0.78 (0.47, 1.28)

16.21

5.18

0.97 (0.81, 1.16)

0.81 (0.60, 1.08)

100.00

51.38

20.47

6.76

1.4 .6 .8 1.2 1.4 1.6 1.8 2

Odds RatioIntensive therapy better Standard therapy better

StudyOdds Ratio

(95% CI)

Weight

(%)

Stroke

Ray KK, et al. Lancet. 2009; 373:1765–72

I2=58% (95% CI 0-84%), p=0.049

Overall

ADVANCE

ACCORD

UKPDS

VADT

PROactive

1.02 (0.87, 1.19)

0.93 (0.82, 1.05)

1.28 (1.06, 1.54)

1.09 (0.81, 1.47)

0.96 (0.77, 1.19)

29.38

23.64

10.05

15.46

21.47

0.79 (0.53, 1.20)

100.00

1.4 .6 .8 1.2 1.4 1.6 1.8 2

Odds RatioIntensive therapy better Standard therapy better

Study

Odds Ratio

(95% CI)Weight

(%)

All-cause mortality

*Included non-fatal myocardial infarction and death from all-cardiac mortality. †Included only non-fatal strokes.

CV risk reduction requires multiple interventions including blood pressure and lipid management

-12,5

-8,2

-2,9

-14

-12

-10

-8

-6

-4

-2

0

Nu

mb

er

of

CV

eve

nts

* p

reve

nte

d

Per 4mmHg lower SBP

Per 1mmol/L lower LDL-C

Per 0.9% lower HbA1c

Benefit of different interventions per 200 diabetic patients treated for 5 years

*Comprised non-fatal myocardial infarction, coronary heart disease, stroke and all-cause mortality

Ray KK, et al. Lancet. 2009;373:1765–72

The vertical dashed line indicates the overall hazard ratio. The size of each square is proportional to the number of patients

ACCORD Study Group. N Engl J Med 2008;358:2545–2559

0.6 1.0 1.4

p value

Favours intensive Favours standard

0.04

0.03

Hazard ratio(95% CI)

Primary outcome

Subgroup

Total

Previous CV event

No

Yes

Glycated haemoglobin at baseline

≤8.0%

>8.0%

ACCORD: intensive glucose control beneficial in patients with no previous CVD or HbA1c <8%

What is the mechanism ?

Summary

• An HbA1c of 6.6 vs 7.5 % over 5y results in

• about a 15% lower risk of CHD

• without an excess mortality risk

• But

• Absolute benefit is modest

Outline

• What treatments reduce the CVD risk in Diabetes?

• Lipid-lowering?

• Blood pressure?

• Glucose-lowering?

• Aspirin?

Effect of aspirin primary prevention of major CVD events in diabetes

De Berardis G et al. BMJ 2009;339:bmj.b4531

Significant increase in risk of bleeding with aspirin

Aspirin: summary for DM patients

• Men- benefit on NFMI

• Women none overall for any endpoint

• Absolute benefits are modest and approximately equal to the risk of bleeding

• For every 10, 000 people Tx in PP about 5 fewer NFMI, but 1 extra haemorrhagic stroke and 3 major bleeds

Conclusions

• When you have it multimodality intervention to reduce macro-vascular and microvascular disease complications

• Prevention is better than cure

Prevention is better than cure!

Tuomilheto NEJM, 2001, 344, 1343-1350